The Seattle Colorectal Cancer Family Registry (CFR), a center within the colon CFR consortium, is a population-based resource for studies of the genetics and genetic epidemiology of colorectal cancer. During 1998-2001, we enrolled incident colorectal cancer cases (n=l,600) identified from the Puget Sound SEER registry, their relatives (n=4,500), and a random sample of population controls (n=1,100). Subjects completed a standardized family history and risk factor interview and provided relevant biospecimens (blood (or buccal) samples and tumor blocks). Tumors have been evaluated for microsatellite instability (MSI) and lymphoblastoid cell lines have been established. These steps have substantially enriched our resource for future research. We are currently conducting several ancillary studies of gene-environment interactions, screening efficacy, behavioral changes, and economics. In this new application, we propose to continue to accrue individuals with colorectal cancer who are at high risk of carrying defective mismatch repair alleles (n=565 individuals less than 50 years), as well as gender and age-matched population controls. This data collection will utilize our established protocols. We will also follow our cohort of probands and their relatives (n=6,090) to measure the risk of developing new polyps and cancers, recurrence of their original cancer, and mortality, as well as behavioral changes. This proposal also includes extensive studies to characterize the colorectal lesions that have been collected, including germline mutations in MLH1 and MSH2 and hypermethylation of the promoter region of MLH1. In collaboration with the other five CFR centers, our registry will be a valuable resource for translational research in the genetic epidemiology of colorectal cancer. The Seattle CFR provides an important population-based perspective within our consortium studies of colorectal cancer.